Over a lifetime approximately 1 in 12 women develops cancer of the breast. While a large majority of these cancers are thought to be sporadic, a proportion of breast cancer cases, often quoted at approximately 5%, is attributable to a predisposition to the disease which is transmitted as a highly penetrant autosomal dominant trait. This usually manifests as familial clustering of early onset breast cancer cases which is often associated with cancers of other organs, notably the ovary.
Abnormalities of several genes are known to confer susceptibility to breast cancer. The BRCA1 gene is located on chromosome 17q21 (1). BRCA1 encodes a 1863 aa protein which contains a RING finger domain and has little other homology to previously characterized proteins (3). Germline mutations of BRCA1 usually result in truncation or absence of the protein and hence presumed inactivation of one or more of its critical functions. BRCA1 accounts for approximately a third of families with cite specific breast cancer. A small proportion of familial breast cancers are attributable to germline mutations in the p53 gene and rare clusters of male breast cancers (4) are due to mutations in the androgen receptor. Work relating to the BRCA1 gene, methods used to isolate it and applications of the BRCA1 nucleic acid and polypeptides are disclosed in EP-A-0705902.
Using families with multiple cases of early onset breast cancer showing evidence against linkage to BRCA.sub.1, the present inventors recently demonstrated the existence of a second major breast cancer susceptibility locus, BRCA2, on chromosome 13q12-q13 (5). Preliminary studies indicate that mutations in BRCA2 confer a similar risk of breast cancer to BRCA1. However, the risk of ovarian cancer appears to be lower and the risk of male breast cancer substantially higher. Together BRCA1 and BRCA2 account for three quarters of families with multiple early onset breast cancer cases, and almost all families with both breast and ovarian cancer.